WO1991019495A1 - Use of a macrolide compound such as fk 506 for manufacturing a medicament for treating idiopathic thrombocytopenic purpura and basedow's disease - Google Patents
Use of a macrolide compound such as fk 506 for manufacturing a medicament for treating idiopathic thrombocytopenic purpura and basedow's disease Download PDFInfo
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- WO1991019495A1 WO1991019495A1 PCT/JP1991/000768 JP9100768W WO9119495A1 WO 1991019495 A1 WO1991019495 A1 WO 1991019495A1 JP 9100768 W JP9100768 W JP 9100768W WO 9119495 A1 WO9119495 A1 WO 9119495A1
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- alkyl
- disease
- basedow
- thrombocytopenic purpura
- idiopathic thrombocytopenic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- This invention relates to a new use of macrolide compounds for idiopathic thrombocytopenic purpura and
- this invention provides a new use of the macrolide compounds for preventing or treating idiopathic thrombocytopenic purpura and Basedow's disease.
- this invention provides a prophylactic or therapeutic agent for idiopathic thrombocytopenic purpura and Basedow's disease, which comprises the macrolide compounds.
- this invention provides a method for preventing or treating idiopathic thrombocytopenic purpura and Basedow's disease, which comprises administering said macrolide compounds to mammals.
- the macrolide compounds used in this invention are known and disclosed, for example, in European Patent
- Those known macrolide compounds include the
- fermentation products such as FR-900506, FR-900520,
- macrolide compounds were indicated inter alia for use in the treatment of rejection to transplantation, autoimmune diseases and infectious diseases.
- the inventors of this invention have surprisingly found that the macrolide compounds mentioned hereinbelow are useful for preventing or treating idiopathic
- the macrolide compounds used in this invention can be represented by the following general formula (I).
- a) represent two vicinal hydrogen atoms
- R 8 and R 9 independently represent H or OH
- n 1, 2 or 3;
- Y, R 10 and R 23 together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-, S- or O-containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and
- Suitable " alkyl” means straight or branched saturated aliphatic hydrocarbon residue and may include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, and the like.
- Suitable " alkenyl” means straight or branched
- unsaturated aliphatic hydrocarbon residue having one double bond may include lower alkenyl such as vinyl, propenyl, butenyl, methylpropenyl, pentenyl, hexenyl, and the like.
- Suitable " aryl” may include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like.
- protected hydroxyl group may include:
- alkylthiomethyl groups e.g. methylthiomethyl
- lower alkyl e.g. cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropion
- alkylcarbamoyl groups having one or more suitable
- substituents such as carboxy or protected carboxy, for example carboxy(lower)alkylcarbamoyl groups( e.g.
- the aromatic acyl group may include aroyl groups which may optionally have one or more suitable substituents such as nitro (e.g. benzoyl, toluoyl, xyloyl, naphthoyl,
- the aromatic group-substituted aliphatic acyl group may include ar(lower)alkanoyl groups which may optionally have one or more suitable substituent(s) such as lower alkoxy and trihalo(lower)alkyl (e.g. phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl2-propoxy-2-phenylacetyl, etc.), and so on.
- suitable substituent(s) e.g. phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl2-propoxy-2-phenylacetyl,
- R 7 is hydrogen, hydroxy, O-lower alkyl such as methoxy or protected hydroxy
- R 10 is methyl, ethyl, propyl or allyl
- R 21 is [R 21 a,H], wherein R 21 a is hydroxy or protected hydroxy;
- X is oxo, (H,OH) or (H,H); Y is oxo; and
- the pharmaceutically acceptable salt of the compound (I) is a nontoxic salt, which may be the corresponding salt with an inorganic or organic base such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.), ammonium salt and amine salts (e.g. triethylamine salt,.
- alkali metal salts e.g. sodium salt, potassium salt, etc.
- alkaline earth metal salts e.g. calcium salt, magnesium salt, etc.
- ammonium salt and amine salts e.g. triethylamine salt,.
- conformers or one pair or more of stereoisomers such as optical and geometrical isomers due to the asymmetric carbon or the double bond.
- Such conformers and isomers also fall within the scope of the invention.
- the macrolide compounds of the present invention may be administered as pure compounds or mixtures of compounds or preferably, in a pharmaceutical vehicle or carrier.
- compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the macrolide compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral,
- the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable, carriers for tablets, pellets, capsules, suppositories, solutions
- the carriers which can be used are water, glucose, lactose, gum. acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
- the active compound is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the disease.
- Mammals which may be treated using the method of the present invention include livestock mammals such as cows, horses, etc. , domestic animals such as dogs, cats, rats, etc. and humans.
- a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg. of the active ingredient is generally given for treating diseases, and an average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg,
- 50 mg, 100 mg, 250 mg and 500 mg is generally administered.
- Daily doses for chronic administration in humans will be in the range of about 0.3 mg/kg/day.
- macrolide compounds (I) used in the present invention are also useful for treating or preventing renal diseases selected from interstitial nephritis,
- nervous diseases selected from multiple myositis
- hematic diseases selected from pure red cell aplasia, aplastic anemia, hypoplastic anemia, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia;
- respiratory diseases selected from sarcoidosis, fibroid lung and idiopathic interstitial pneumonia;
- skin diseases selected from dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma;
- Croscarmellose sodium (Ac-Di-Sol) 1 g
- the FK 506 (1 g) was dissolved in ethanol (10 ml), and thereto was added hydroxypropyl methylcellulose 2910 (TC-5R) (1 g) to prepare a suspension.
- TC-5R hydroxypropyl methylcellulose 2910
- dichloromethane 5 ml
- Lactose (2 g) and croscarmellose sodium (Trade Mark:
- a tablet was prepared in a conventional manner by using the solid dispersion composition (49.75 mg) mentioned above and magnesium stearate (0.25 mg) .
- the tablet prepared in (1) was coated with the composition containing the following compounds in a conventional manner. Titanium oxide 0.85 mg
Abstract
Macrolide compounds such as the FR-900506 and its related compounds are provided for the prevention or treatment of idiopathic thrombocytopenic purpura and Basedow's disease. Composition containing such compounds is also disclosed.
Description
DESCRIPTION
USE OF A MACROLIDE COMPOUND SUCH AS FK 506 FOR MANUFACTURING A MEDICAMENT FOR TREATING IDIOPATHIC THROMBOCYTOPENIC PURPURA
AND BASEDOW'S DISEASE
This invention relates to a new use of macrolide compounds for idiopathic thrombocytopenic purpura and
Basedow's disease.
Accordingly, this invention provides a new use of the macrolide compounds for preventing or treating idiopathic thrombocytopenic purpura and Basedow's disease.
Further, this invention provides a prophylactic or therapeutic agent for idiopathic thrombocytopenic purpura and Basedow's disease, which comprises the macrolide compounds.
Still further, this invention provides a method for preventing or treating idiopathic thrombocytopenic purpura and Basedow's disease, which comprises administering said macrolide compounds to mammals.
The macrolide compounds used in this invention are known and disclosed, for example, in European Patent
Publication No. 0184162 and International Publication No. WO 89/05304.
Those known macrolide compounds include the
fermentation products, such as FR-900506, FR-900520,
FR-900523 and FR-900525, isolated from microorganisms belonging to genus Streptomyces, such as Streptomyces tsukubaensis No. 9993 (FERM BP-927) or Streptomyces
hygroscopicus subsp. yakushimaensis No. 7238 (FERM BP-928), and their related compounds prepared from these fermentation products.
These macrolide compounds were indicated inter alia for use in the treatment of rejection to transplantation, autoimmune diseases and infectious diseases.
The inventors of this invention have surprisingly found
that the macrolide compounds mentioned hereinbelow are useful for preventing or treating idiopathic
thrombocytopenic purpura and Basedow's disease.
The macrolide compounds used in this invention can be represented by the following general formula (I).
a) represent two vicinal hydrogen atoms, or
b) form a second bond between the vicinal carbon atoms to which they are attached;
in addition to its significance above, R2 may represent an alkyl group;
R7 represents H, OH, protected hydroxy or O-alkyl, or in conjunction with R1 it may represent =O;
R8 and R9 independently represent H or OH;
R10 represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or
more hydroxyl groups, or alkyl substituted by =O;
X represents O, (H,OH), (H,H) or -CH2O-;
Y represents O, (H,OH), (H,H), N-NR11R12 or N-OR13;
R11 and R12 independently represent H, alkyl, aryl or tosyl;
R13, R14, R15, R16, R17, R18, R19, R22 and R23
independently represent H or alkyl;
R20 and R21 independently represent O, or they may independently represent (R20a,H) and (R21a,H) respectively; R20a and R21a independently represent OH, O-alkyl or
OCH2OCH2CH2OCH3 or R21a is protected hydroxy;
in addition, R20a and R21a may together represent an oxygen atom in an epoxide ring;
n is 1, 2 or 3;
in addition to their significances above, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-, S- or O-containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and
-CH2Se(C6H5).
The specific examples of the definitions of compound (I) and the preferred working modes of the invention are described in detail below.
The term " lower " as used in this specification means, unless otherwise indicated, any number of carbon atoms between 1 and 6, inclusive.
Suitable " alkyl " means straight or branched saturated aliphatic hydrocarbon residue and may include lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl, hexyl, and the like.
Suitable " alkenyl " means straight or branched
unsaturated aliphatic hydrocarbon residue having one double bond and may include lower alkenyl such as vinyl, propenyl, butenyl, methylpropenyl, pentenyl, hexenyl, and the like.
Suitable " aryl " may include phenyl, tolyl, xylyl, cumenyl, mesityl, naphthyl, and the like.
Suitable examples of the protective group in the
" protected hydroxyl group " may include:
1-(lower alkylthio) (lower)alkyl groups such as lower
alkylthiomethyl groups (e.g. methylthiomethyl,
ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), more desirably C1-C4 alkylthiomethyl groups, and most desirably methylthiomethyl;
tri-substituted silyl groups such as tri(lower)-alkylsilyl groups (e.g. trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyl-dimethylsilyl,
tri-tert-butylsilyl, etc.);
lower alkyl-diarylsilyl groups (e.g. methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenylsilyl, etc.), more desirably tri(C1-C4)alkylsilyl and C1-C4 alkyldiphenylsilyl groups and most desirably tert-butyldimethylsilyl and tert-butyldiphenylsilyl; and acyl groups such as aliphatic acyl groups, aromatic acyl groups and aliphatic acyl. groups substituted by aromatic groups, which are derived from carboxylic acids, sulfonic acids or carbamic acids.
The aliphatic acyl group may includes lower alkanoyl groups which may optionally have one or more suitable substituents such as carboxy (e.g. formyl, acetyl,
propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl, etc.), cyclo(lower)alkoxy- (lower)alkanoyl groups which may optionally have one or more appropriate substituents such as lower alkyl (e.g.
cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl,
menthyloxyhexanoyl, etc.), camphorsulfonyl, lower
alkylcarbamoyl groups having one or more suitable
substituents such as carboxy or protected carboxy, for example carboxy(lower)alkylcarbamoyl groups( e.g.
carboxymethylcarbamoyl, carboxyethylcarbamoyl,
carboxypropylcarbamoyl, carboxybutylcarbamoyl,
carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc.), protected carboxy(lower)alkylcarbamoyl groups such as tri (lower)alkylsilyl(lower)alkoxycarbonyl(lower)alkylcarbamoyl groups(e.g. trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropyl
carbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl, etc.) and so on.
The aromatic acyl group may include aroyl groups which may optionally have one or more suitable substituents such as nitro (e.g. benzoyl, toluoyl, xyloyl, naphthoyl,
nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc),
arenesulfonyl groups which may optionally have one or more suitable substituent(s) such as halogen (e.g.
benzenesulfonyl, toluenesulfonyl, xylenesulfonyl,
naphthalenesulfonyl, fluorobenzenesulfonyl,
chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.), and so on.
The aromatic group-substituted aliphatic acyl group may include ar(lower)alkanoyl groups which may optionally have one or more suitable substituent(s) such as lower alkoxy and trihalo(lower)alkyl (e.g. phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2-trifluoromethyl2-propoxy-2-phenylacetyl, etc.), and so on.
Among the above-mentioned acyl groups, the more
desirable acyl groups are C1-C4 alkanoyl groups which may optionally be substituted by carboxy, cyclo(C5-C6)alkyloxy-(C1-C4)alkanoyl groups having two (C1-C4)alkyl groups in the cycloalkyl moiety, camphorsulfonyl, carboxy(C1-C4)alkylcarbamoyl groups, tri(C1-C4)alkylsilyl(C1-C4)alkoxycarbonyl-(C1-C4)alkylcarbamoyl groups, benzoyl which may have one or two nitro groups, halogen-substituted benzenesulfonyl groups, phenyl(C1-C4)alkanoyl groups having C1-C4 alkoxy and trihalo(C1-C4)alkyl groups. Of these groups, the most desirable are acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2-methoxy-2-phenylacetyl.
Suitable " 5- or 6-membered N-, S- or O-containing heterocyclic ring " may include pyrrolyl, tetrahydrofuryl, and the like.
Preferred embodiments of the Symbols R1 to R10, R14 to R23, x, y and n are as follows..
R1 and R2 are each hydrogen or combined to form a second bond;
R3 and R4 are combined to form a second bond;
R5 and R6 are combined to form a second bond;
R7 is hydrogen, hydroxy, O-lower alkyl such as methoxy or protected hydroxy;
R8 is hydrogen;
R9 is hydroxy;
R10 is methyl, ethyl, propyl or allyl;
R14, R15, R16, R17, R18 and R19 are each methyl;
R20 is oxo or [R20a,H], wherein R20a is hydroxy or methoxy;
R21 is [R21a,H], wherein R21a is hydroxy or protected hydroxy;
R23 is hydrogen;
X is oxo, (H,OH) or (H,H);
Y is oxo; and
n is 1 or 2.
The pharmaceutically acceptable salt of the compound (I) is a nontoxic salt, which may be the corresponding salt with an inorganic or organic base such as alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.), ammonium salt and amine salts (e.g. triethylamine salt,.
N-benzyl-N-methylamine salt, etc.) and so on.
Referring to compound (I), there may exist conformers or one pair or more of stereoisomers such as optical and geometrical isomers due to the asymmetric carbon or the double bond. Such conformers and isomers also fall within the scope of the invention.
Particularly, the most interesting compound is
FR-900506 of the following formula.
(hereinafter, described as FK506)
The macrolide compounds of the present invention may be administered as pure compounds or mixtures of compounds or preferably, in a pharmaceutical vehicle or carrier.
The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the macrolide compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral,
intravenous, intramuscular, or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable, carriers for tablets, pellets, capsules, suppositories, solutions
(saline, for example), emulsion, suspensions (olive oil, for example) , and any other form suitable for use. The carriers which can be used are water, glucose, lactose, gum. acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active compound is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the disease.
Mammals which may be treated using the method of the present invention include livestock mammals such as cows, horses, etc. , domestic animals such as dogs, cats, rats, etc. and humans.
For applying this composition to a human, it is
preferable to apply it by oral, parenteral, external, enteral, intravenous, or intramuscular administration.
While the dosage of therapeutically effective amount of the macrolide compounds varies from and also depends upon
the age and condition of each individual patient to be treated, a daily dose of about 0.01-1000 mg, preferably 0.1-500 mg and more preferably 0.5-100 mg. of the active ingredient is generally given for treating diseases, and an average single dose of about 0.2-0.5 mg, 1 mg, 5 mg, 10 mg,
50 mg, 100 mg, 250 mg and 500 mg is generally administered.
Daily doses for chronic administration in humans will be in the range of about 0.3 mg/kg/day.
Further, the macrolide compounds (I) used in the present invention are also useful for treating or preventing renal diseases selected from interstitial nephritis,
Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy;
nervous diseases selected from multiple myositis,
Guillain-Barré syndrome, Ménière's disease and
radiculopathy;
endocrine diseases selected from hyperthyroidism;
hematic diseases selected from pure red cell aplasia, aplastic anemia, hypoplastic anemia, autoimmune hemolytic anemia, agranulocytosis and anerythroplasia;
bone diseases such as osteoporosis;
respiratory diseases selected from sarcoidosis, fibroid lung and idiopathic interstitial pneumonia;
eye diseases selected from herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukmas, ocular pemphigus, Mooren's ulcer, scleritis and Grave's ophthalmopathy;
skin diseases selected from dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma;
circulatory diseases selected from arteriosclerosis,
aortitis syndrome, polyarteritis nodosa and myocardosis;
collagen diseases selected from scleroderma, Wegener's granuloma and Sjogren's syndrome;
adiposis;
eosinophilic fasciitis;
periodontal disease;
muscular dystrophy; and so on. And further, it is considered that the compounds described in the European Patent Publication Nos. 0349049, 0349061, 0358508, 0364031, 0364032, 0378317, 0378320,
037321, 0388153, 0396399, 0396400, 0399579, 0403242,
0356399, 0402931, 0353678; British Patent Publication No. 2225576; International Patent Application Nos.
PCT/GB90/01262 and PCT/JP91/00314; Japanese Patent
Application No. 3-53588 (1991), and so on, are also useful for the diseases shown in the present specification. The following examples are given for the purpose of illustrating the present invention.
Example 1 FK 506 1 g
Hydroxypropyl methylcellulose 2910 (TC-5R) 1 g
Lactose 2 g
Croscarmellose sodium (Ac-Di-Sol) 1 g The FK 506 (1 g) was dissolved in ethanol (10 ml), and thereto was added hydroxypropyl methylcellulose 2910 (TC-5R) (1 g) to prepare a suspension. To this suspension was added dichloromethane (5 ml) to prepare a homogeneous solution. Lactose (2 g) and croscarmellose sodium (Trade Mark:
Ac-Di-Sol, maker: Asahi Chemical Industry) were
homogeneously suspended to this solution, and then the organic solvent was removed by evaporation. The residual product was dried under reduced pressure for 10 hours by vacuum dryer, milled for 2 minutes by coffee mill and then passed through a sieve (32 mesh) to give the solid
dispersion composition of FK 506 (5 g) (hereinafter, described as SDF). This composition was capsulated by a conventional manner to provide capsules containing 1 mg or 5 mg of FK 506 per each capsule.
Example 2
1mg-Capsule 5mg-Capsule
SDF 5 mg 25 mg
Lactose 59.15 mg 113.6 mg
Magnesium stearate 0.65 mg 1.4 mg The above-mentioned compounds were capsulated by a conventional manner to provide lmg- or 5mg-Capsules
respectively, in which SDF was prepared in a similar manner to that of Example 1.
Example 3
(1) The solid dispersion composition containing the following compounds were prepared in a similar manner to that of Example 1.
FK 506 10.0 mg
Hydroxypropyl methylcellulose 2910 (TC-5R) 10.0 mg
Lactose 19.75 mg
Croscarmellose sodium (Ac-Di-Sol) 10.0 mg
And a tablet was prepared in a conventional manner by using the solid dispersion composition (49.75 mg) mentioned above and magnesium stearate (0.25 mg) .
(2) The tablet prepared in (1) was coated with the composition containing the following compounds in a conventional manner. Titanium oxide 0.85 mg
Hydroxypropyl methylcellulose 2910 (TC-5R) 1.90 mg Macrogol 6000 0.25 mg
Claims
1. A use of macrolide compounds of the formula;
[R3 and R4], [R5 and R6] independently
a) represent two vicinal hydrogen atoms, or b) form a second bond between the vicinal
carbon atoms to which they are attached; in addition to its significance above, R2 may represent an alkyl group;
R7 represents H, OH, protected hydroxy or
O-alkyl, or in conjunction with R1 it may represent =O;
R8 and R9 independently represent H or OH; R10 represents H, alkyl, alkyl substituted by one or more hydroxyl groups, alkenyl, alkenyl substituted by one or more hydroxyl groups, or alkyl substituted by =O;
X represents O, (H,OH), (H,H) or -CH2O-;
Y represents O, (H,OH), (H,H), N-NR11R12 or
N-OR13;
R11 and R12 independently represent H, alkyl, aryl or tosyl;
R13, R14, R15, R16, R17, R18, R19, R22 and R23 independently represent H or alkyl;
R20 and R21 independently represent O, or they may independently represent (R20a,H) and (R21a,H) respectively; R20a and R21a
independently represent OH, O-alkyl or
OCH2OCH2CH2OCH3 or R21a is protected
hydroxy;
in addition, R20a and R21a may together represent an oxygen atom in an epoxide ring; n is 1, 2 or 3;
in addition to their significances above, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a 5- or 6- membered N-, S- or O- containing heterocyclic ring, which may be saturated or unsaturated, and which may be substituted by one or more groups selected from alkyl, hydroxy, alkyl substituted by one or more hydroxyl groups, O-alkyl, benzyl and -CH2Se(C6H5);
or a pharmaceutically acceptable salt thereof, for preventing or treating idiopathic thrombocytopenic purpura and Basedow's disease.
2. A use of the macrolide compounds (I) defined in Claim 1 as a prophylactic or therapeutic agent for idiopathic thrombocytopenic purpura and Basedow's disease.
3. A prophylactic or therapeutic agent for idiopathic
thrombocytopenic purpura and Basedow's disease, which comprises the macrolide compounds (I) defined in Claim 1.
4. A method for preventing or treating idiopathic
thrombocytopenic purpura and Basedow's disease,
which comprises administering the macrolide compounds (I) defined in claim 1 to mammals.
5. A use of the macrolide compounds (I) defined in claim 1 for manufacturing a medicament for preventing or treating idiopathic thrombocytopenic purpura and Basedow's
disease.
6. A pharmaceutical composition for idiopathic
thrombocytopenic purpura and Basedow's disease,
which comprises the macrolide compounds (I) defined in
Claim 1 in admixture with a carrier or excipient.
7. A process for preparing the pharmaceutical composition of Claim 6, which is characterized by admixing the macrolide compounds (I) with a carrier or excipient.
8. The macrolide compound used in Claims 1 to 7 is FK 506.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP91510110A JPH05507915A (en) | 1990-06-11 | 1991-06-07 | Application of macrolide compounds such as FK506 for the production of therapeutic agents for idiopathic thrombocytopenic purpura and Graves' disease |
Applications Claiming Priority (26)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9012955.2 | 1990-06-11 | ||
GB909012958A GB9012958D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for hematic diseases |
GB9012942.0 | 1990-06-11 | ||
GB909012951A GB9012951D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for collagen diseases |
GB9012958.6 | 1990-06-11 | ||
GB909012942A GB9012942D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for eosinophilic fasciitis |
GB909012954A GB9012954D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for skin diseases |
GB9012953.7 | 1990-06-11 | ||
GB9012961.0 | 1990-06-11 | ||
GB909012960A GB9012960D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for nervous diseases |
GB909012955A GB9012955D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for eye diseases |
GB9012959.4 | 1990-06-11 | ||
GB9012954.5 | 1990-06-11 | ||
GB909012956A GB9012956D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for respiratory diseases |
GB909012961A GB9012961D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for renal diseases |
GB9012951.1 | 1990-06-11 | ||
GB909012953A GB9012953D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for circulatory diseases |
GB909012952A GB9012952D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for adiposis |
GB9012957.8 | 1990-06-11 | ||
GB9012956.0 | 1990-06-11 | ||
GB9012960.2 | 1990-06-11 | ||
GB9012952.9 | 1990-06-11 | ||
GB909012957A GB9012957D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for bone diseases |
GB909012959A GB9012959D0 (en) | 1990-06-11 | 1990-06-11 | New use of macrolide compounds for endocrine diseases |
GB9017701.5 | 1990-08-13 | ||
GB909017701A GB9017701D0 (en) | 1990-08-13 | 1990-08-13 | New use of macrolide compounds for periodontal disease |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1991019495A1 true WO1991019495A1 (en) | 1991-12-26 |
Family
ID=27584060
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1991/000768 WO1991019495A1 (en) | 1990-06-11 | 1991-06-07 | Use of a macrolide compound such as fk 506 for manufacturing a medicament for treating idiopathic thrombocytopenic purpura and basedow's disease |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP0533930A1 (en) |
JP (1) | JPH05507915A (en) |
WO (1) | WO1991019495A1 (en) |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0515071A2 (en) | 1991-05-13 | 1992-11-25 | Merck & Co. Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity |
LT3533B (en) | 1991-09-09 | 1995-11-27 | Merck & Co Inc | O-heyteroaryl, o-alkylheteroaryl, o-alkenylheteroaryl and o-alkynylheteroaryl macrolides |
US5686424A (en) * | 1992-04-08 | 1997-11-11 | Miles Inc. | 2-oxoethyl derivatives as immunosuppressants |
US5925649A (en) * | 1995-04-06 | 1999-07-20 | Novartis Ag | Ascomycins |
US5932243A (en) * | 1993-05-27 | 1999-08-03 | Novartis Ag | Galenical formulations |
AT408520B (en) * | 1993-05-27 | 2001-12-27 | Novartis Erfind Verwalt Gmbh | Pharmaceutical formulations |
US6352998B2 (en) | 1994-10-26 | 2002-03-05 | Novartis Ag | Pharmaceutical compositions |
WO2004016258A1 (en) * | 2002-08-14 | 2004-02-26 | Mondobiotech Laboratories Anstalt | Therapeutical use of guanylhydrazones for treating diseases associated with dendritic cell maturation |
US6872383B2 (en) | 1999-04-30 | 2005-03-29 | Sucampo Ag | Use of macrolide compounds for the treatment of dry eye |
US7014227B2 (en) * | 2003-05-09 | 2006-03-21 | The Langenau Manufacturing Company | Wedge bar locking mechanism |
US7273874B2 (en) | 2004-12-20 | 2007-09-25 | Wyeth | Rapamycin derivatives and the uses thereof in the treatment of neurological disorders |
US7276498B2 (en) | 2004-12-20 | 2007-10-02 | Wyeth | Rapamycin analogues and uses thereof in the treatment of neurological disorders |
WO2009054463A1 (en) | 2007-10-25 | 2009-04-30 | Astellas Pharma Inc. | Pharmaceutical composition containing lipophilic il-2 production inhibitor |
EP2198858A1 (en) | 1998-03-26 | 2010-06-23 | Astellas Pharma Inc. | Sustained release preparation of a macrolide compound like tacrolimus |
EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
US9402802B2 (en) | 1998-12-03 | 2016-08-02 | Meda Pharma Sarl | Topical compositions comprising ascomycins |
CN106074367A (en) * | 2016-07-20 | 2016-11-09 | 中山大学中山眼科中心 | Containing FK506 compounds/dimeric pharmaceutical composition of FKBP albumen and preparation method thereof |
WO2020032252A1 (en) | 2018-08-10 | 2020-02-13 | 晃史 山口 | Therapeutic agent for humoral immunity-related diseases in materno-fetal relationship |
WO2020129348A1 (en) | 2018-12-18 | 2020-06-25 | 晃史 山口 | Agent for improving infertility, recurrent miscarriage, and state of pregnancy |
EP3977995A1 (en) | 2014-10-28 | 2022-04-06 | Koushi Yamaguchi | Tacrolimus for ameliorating pregnancy conditions |
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EP0184162A2 (en) * | 1984-12-03 | 1986-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
EP0323042A1 (en) * | 1987-12-09 | 1989-07-05 | FISONS plc | Process to macrocyclic compounds |
WO1990004398A1 (en) * | 1988-10-28 | 1990-05-03 | Klaus Bendtzen | A new pharmaceutical use of fusidic acid and derivatives thereof |
-
1991
- 1991-06-07 WO PCT/JP1991/000768 patent/WO1991019495A1/en not_active Application Discontinuation
- 1991-06-07 EP EP91911491A patent/EP0533930A1/en not_active Withdrawn
- 1991-06-07 JP JP91510110A patent/JPH05507915A/en active Pending
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EP0184162A2 (en) * | 1984-12-03 | 1986-06-11 | Fujisawa Pharmaceutical Co., Ltd. | Tricyclo compounds, a process for their production and a pharmaceutical composition containing the same |
EP0323042A1 (en) * | 1987-12-09 | 1989-07-05 | FISONS plc | Process to macrocyclic compounds |
WO1990004398A1 (en) * | 1988-10-28 | 1990-05-03 | Klaus Bendtzen | A new pharmaceutical use of fusidic acid and derivatives thereof |
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"The Merck Manual", 15 edition, 1987, pages 1038-1043, Merck & Co., Inc., Rahway, NJ, US, see pages 1038-1043,1159-1160 * |
CURRENT OPINION IN IMMUNOLOGY, vol. 2, no. 6, 1990, Current Biology Ltd, St.J. COLLIER: "Immunosuppressive drugs", pages 854-858, see the whole article * |
IMMUNOLOGY TODAY, vol. 10, no. 1, January 1989, A.W. THOMSON: "FK-506 - How much potential?", pages 1-32, see the whole article * |
IMMUNOLOGY, vol. 69, no. 2, February 1990, K. YAMAMOTO et al.: "Experimental treatment of autoimmune MRL-lpr/lpr mice with immunosuppressive compound FK506", pages 222-227, see the whole article * |
KLINISCHE WOCHENSCHRIFT, vol. 68, (suppl. XXI):III, 1990, (Pathophysiology and Pharmacotherapy of Autoimmune Diseases, Satellite Symposium, 29 July 1989), Springer-Verlag, D.B.J. HERRMANN et al.: "Drugs in autoimmune diseases", pages 15-25, see the whole article, in particular page 17 * |
Cited By (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0515071A2 (en) | 1991-05-13 | 1992-11-25 | Merck & Co. Inc. | O-aryl, O-alkyl, O-alkenyl and O-alkynylmacrolides having immunosuppressive activity |
LT3533B (en) | 1991-09-09 | 1995-11-27 | Merck & Co Inc | O-heyteroaryl, o-alkylheteroaryl, o-alkenylheteroaryl and o-alkynylheteroaryl macrolides |
US5686424A (en) * | 1992-04-08 | 1997-11-11 | Miles Inc. | 2-oxoethyl derivatives as immunosuppressants |
US6565859B1 (en) | 1993-05-27 | 2003-05-20 | Novartis Ag | Galenical formulations |
AT408521B (en) * | 1993-05-27 | 2001-12-27 | Novartis Erfind Verwalt Gmbh | PHARMACEUTICAL ORAL COMPOSITION CONTAINING RAPAMYCIN CLASS COMPOUNDS |
AT408520B (en) * | 1993-05-27 | 2001-12-27 | Novartis Erfind Verwalt Gmbh | Pharmaceutical formulations |
US5932243A (en) * | 1993-05-27 | 1999-08-03 | Novartis Ag | Galenical formulations |
US7025975B2 (en) | 1993-05-27 | 2006-04-11 | Novartis Ag | Galenical formulations |
US6352998B2 (en) | 1994-10-26 | 2002-03-05 | Novartis Ag | Pharmaceutical compositions |
US5925649A (en) * | 1995-04-06 | 1999-07-20 | Novartis Ag | Ascomycins |
EP2198858A1 (en) | 1998-03-26 | 2010-06-23 | Astellas Pharma Inc. | Sustained release preparation of a macrolide compound like tacrolimus |
US8551522B2 (en) | 1998-03-26 | 2013-10-08 | Astellas Pharma Inc. | Sustained-release formulation |
US9402802B2 (en) | 1998-12-03 | 2016-08-02 | Meda Pharma Sarl | Topical compositions comprising ascomycins |
US6872383B2 (en) | 1999-04-30 | 2005-03-29 | Sucampo Ag | Use of macrolide compounds for the treatment of dry eye |
US7063857B1 (en) | 1999-04-30 | 2006-06-20 | Sucampo Ag | Use of macrolide compounds for the treatment of dry eye |
WO2004016258A1 (en) * | 2002-08-14 | 2004-02-26 | Mondobiotech Laboratories Anstalt | Therapeutical use of guanylhydrazones for treating diseases associated with dendritic cell maturation |
US7014227B2 (en) * | 2003-05-09 | 2006-03-21 | The Langenau Manufacturing Company | Wedge bar locking mechanism |
EP2583678A2 (en) | 2004-06-24 | 2013-04-24 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
US7273874B2 (en) | 2004-12-20 | 2007-09-25 | Wyeth | Rapamycin derivatives and the uses thereof in the treatment of neurological disorders |
US7560457B2 (en) | 2004-12-20 | 2009-07-14 | Wyeth | Rapamycin analogues and the uses thereof in the treatment of neurological, proliferative, and inflammatory disorders |
US7795252B2 (en) | 2004-12-20 | 2010-09-14 | Pfizer Inc. | Rapamycin analogues and the uses thereof in the treatment of neurological, proliferative, and inflammatory disorders |
US7476678B2 (en) | 2004-12-20 | 2009-01-13 | Wyeth | Rapamycin derivatives and the uses thereof in the treatment of neurological disorders |
US7470682B2 (en) | 2004-12-20 | 2008-12-30 | Wyeth | Rapamycin analogues and the uses thereof in the treatment of neurological disorders |
US7276498B2 (en) | 2004-12-20 | 2007-10-02 | Wyeth | Rapamycin analogues and uses thereof in the treatment of neurological disorders |
WO2009054463A1 (en) | 2007-10-25 | 2009-04-30 | Astellas Pharma Inc. | Pharmaceutical composition containing lipophilic il-2 production inhibitor |
EP3977995A1 (en) | 2014-10-28 | 2022-04-06 | Koushi Yamaguchi | Tacrolimus for ameliorating pregnancy conditions |
CN106074367A (en) * | 2016-07-20 | 2016-11-09 | 中山大学中山眼科中心 | Containing FK506 compounds/dimeric pharmaceutical composition of FKBP albumen and preparation method thereof |
WO2020032252A1 (en) | 2018-08-10 | 2020-02-13 | 晃史 山口 | Therapeutic agent for humoral immunity-related diseases in materno-fetal relationship |
WO2020129348A1 (en) | 2018-12-18 | 2020-06-25 | 晃史 山口 | Agent for improving infertility, recurrent miscarriage, and state of pregnancy |
Also Published As
Publication number | Publication date |
---|---|
JPH05507915A (en) | 1993-11-11 |
EP0533930A1 (en) | 1993-03-31 |
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